The hSNM1B/Apollo variant rs11552449 is associated with cellular sensitivity towards mitomycin C and ionizing radiation

Herwest, Sarah; Albers, C.; Schmiester, Maren; Salewsky, Bastian; Hopfenmüller, Werner; Meyer, Antje; Bertram, Lars; Demuth, Ilja

doi:10.1016/j.dnarep.2018.09.004

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…Our study on the structure, and properties, of the breast cancer associated, H61Y variant of SNM1B 1–355 reveal its fold is very similar to unliganded WT SNM1B 1–355 and appears equivalent to WT SNM1B 1–355 with regards to thermal stability, DNA binding, catalytic efficiency, and nuclease activity. The H61Y SNP ( rs11552449 ) is associated with cancer risk due to its correlation with alternative splicing of the SNM1B and PHTF1 transcripts, each also associated with increased cancer risk ( 30 ) and (for the SNM1B transcript) to cellular sensitivity towards mitomycin C and IR ( 52 ). Thus, it would seem likely that the reported deleterious associations of rs11552449 and cancer risk may be mediated by the effects of alternative transcript splicing, rather than the non-synonymous substitution in the protein-coding sequence.…”

Section: Discussionmentioning

confidence: 99%

A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family

Baddock

Newman

Yosaatmadja

et al. 2021

Nucleic Acids Research

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The SNM1 nucleases which help maintain genome integrity are members of the metallo-β-lactamase (MBL) structural superfamily. Their conserved MBL-β-CASP-fold SNM1 core provides a molecular scaffold forming an active site which coordinates the metal ions required for catalysis. The features that determine SNM1 endo- versus exonuclease activity, and which control substrate selectivity and binding are poorly understood. We describe a structure of SNM1B/Apollo with two nucleotides bound to its active site, resembling the product state of its exonuclease reaction. The structure enables definition of key SNM1B residues that form contacts with DNA and identifies a 5′ phosphate binding pocket, which we demonstrate is important in catalysis and which has a key role in determining endo- versus exonucleolytic activity across the SNM1 family. We probed the capacity of SNM1B to digest past sites of common endogenous DNA lesions and find that base modifications planar to the nucleobase can be accommodated due to the open architecture of the active site, but lesions axial to the plane of the nucleobase are not well tolerated due to constriction around the altered base. We propose that SNM1B/Apollo might employ its activity to help remove common oxidative lesions from telomeres.

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Section: Discussionmentioning

confidence: 99%

A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family

Baddock

Newman

Yosaatmadja

et al. 2021

Nucleic Acids Research

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“…To investigate TL-dependent expression of PPP2R2C in a different human cell type, we assessed the expression of PPP2R2C and TLs in 413 lymphoblastoid cell lines (LCLs) established from B lymphocytes from participants of the Berlin Aging Study II (BASE-II) ( 43 , 44 ), using the reverse transcription PCR (RT-PCR) and monochrome multiplex quantitative PCR (MMqPCR) approaches used for fibroblasts above. LCLs are expected to represent cells with a very broad TL distribution.…”

Section: Resultsmentioning

confidence: 99%

A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts

et al. 2022

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Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies.

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“…Besides, DCLRE1B has been interconnected to DNA lesion repair, specifically interstrand crosslinks (ICLs) and double-strand breaks (DSBs). Repair of DNA damage caused by ICL necessitates DCLRE1B, and its absence enhances sensitivity to agents that induce ICL, comprising mitomycin C and cisplatin C [ 3 ]. In addition, high expression of DCLRE1B gene in renal, liver and pancreatic cancers resulted in poor prognosis [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

DCLRE1B promotes tumor progression and predicts immunotherapy response through METTL3-mediated m6A modification in pancreatic cancer

Li,

Wang,

Deng

et al. 2023

BMC Cancer

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Background DCLRE1B is a 5’-to-3’ exonuclease, which is involved in repairing ICL-related DNA damage. DCLRE1B has been reported to cause poor prognosis in a variety of cancers. Nonetheless, there is no research on DCLRE1B’s biological role in pan-cancer datasets. Thus, ascertaining the processes via which DCLRE1B modulates tumorigenesis was the goal of the extensive bioinformatics investigation of pan-cancer datasets in the present research. Methods In our research, employing internet websites and databases including TIMER, GEPIA, TISIDB, Kaplan–Meier Plotter, SangerBox, cBioPortal, and LinkedOmics, DCLRE1B-related data in numerous tumors were extracted. To ascertain the association among DCLRE1B expression, prognosis, genetic changes, and tumor immunity, the pan-cancer datasets were examined. The DCLRE1B’s biological roles in pancreatic cancer cells were ascertained by employing wound healing, in vitro CCK-8, and MeRIP-qPCR assays. Result According to the pan-cancer analysis, in numerous solid tumors, DCLRE1B upregulation was observed. Expression of DCLRE1B was found to be substantially related to the cancer patients’ prognoses. Similarly, expression of DCLRE1B exhibited substantial association with immune cells in several cancer types. DCLRE1B expression correlated with immune checkpoint (ICP) gene expression and impacted immunotherapy sensitivity. According to in vitro trials, DCLRE1B promoted PC cells’ proliferation and migration capacities. Also, according to GSEA enrichment analysis, DCLRE1B might participate in the JAK-STAT signaling pathway, which was confirmed by western blotting. In addition, we also found that the downregulation of DCLRE1B may be regulated by METTL3-mediated m6A modification. Conclusions In human cancer, the overexpression of DCLRE1B was generally observed, which aided cancer onset and advancement via a variety of processes comprising control of the immune cells’ tumor infiltration. According to this study’s findings, in a few malignant tumors, DCLRE1B is a candidate immunotherapeutic and prognostic biomarker.

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The hSNM1B/Apollo variant rs11552449 is associated with cellular sensitivity towards mitomycin C and ionizing radiation

Cited by 6 publications

References 30 publications

A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family

A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family

A conserved long-distance telomeric silencing mechanism suppresses mTOR signaling in aging human fibroblasts

DCLRE1B promotes tumor progression and predicts immunotherapy response through METTL3-mediated m6A modification in pancreatic cancer

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